Compounds useful for treating allergic and inflammatory diseases

ABSTRACT

Novel compounds or formula (I) are described herein. These compounds inhibit the production of Tumor Necrosis Factor and are useful in the treatment of disease states mediated or exacerbated by TNF production. The compounds or the present invention are also useful in the mediation or inhibition of enzymatic or catalytic activity of phosphodiesterase IV and are therefore useful in the treatment of disease states in need of mediation or inhibition therefore. ##STR1##

This application is a continuation of PCT application PCT/US93/01991filed 2 Apr. 1993, now WO93/19749; which is a continuation-in-part ofU.S. Pat. No. 07/968,762 filed 30 Oct. 1992, now abandoned; which is acontinuation-in-part of U.S. Pat. No. 07/862,030 filed 2 Apr. 1992, nowabandoned.

FIELD OF INVENTION

The present invention relates to novel compounds, pharmaceuticalcompositions containing these compounds, and their use in treatingallergic and inflammatory diseases and for inhibiting the production ofTumor Necrosis Factor (TNF).

BACKGROUND OF THE INVENTION

Bronchial asthma is a complex, multifactorial disease characterized byreversible narrowing of the airway and hyperreactivity of therespiratory tract to external stimuli.

Identification of novel therapeutic agents for asthma is made difficultby the fact that multiple mediators are responsible for the developmentof the disease. Thus, it seems unlikely that eliminating the effects ofa single mediator will have a substantial effect on all three componentsof chronic asthma. An alternative to the "mediator approach" is toregulate the activity of the cells responsible for the pathophysiologyof the disease.

One such way is by elevating levels of cAMP (adenosine cyclic 3',5'-monophosphate). Cyclic AMP has been shown to be a second messengermediating the biologic responses to a wide range of hormones,neurotransmitters and drugs; [Krebs Endocrinology Proceedings of the 4thInternational Congress Excerpta Medica, 17-29, 1973]. When theappropriate agonist binds to specific cell surface receptors, adenylatecyclase is activated, which converts Mg⁺² -ATP to cAMP at an acceleratedrate.

Cyclic AMP modulates the activity of most, if not all, of the cells thatcontribute to the pathophysiology of extrinsic (allergic) asthma. Assuch, an elevation of cAMP would produce beneficial effectsincluding: 1) airway smooth muscle relaxation, 2) inhibition of mastcell mediator release, 3) suppression of neutrophil degranulation, 4)inhibition of basophil degranulation, and 5) inhibition of monocyte andmacrophage activation. Hence, compounds that activate adenylate cyclaseor inhibit phosphodiesterase should be effective in suppressing theinappropriate activation of airway smooth muscle and a wide variety ofinflammatory cells. The principal cellular mechanism for theinactivation of cAMP is hydrolysis of the 3'-phosphodiester bond by oneor more of a family of isozymes referred to as cyclic nucleotidephosphodiesterases (PDEs).

It has now been shown that a distinct cyclic nucleotidephosphodiesterase (PDE) isozyme, PDE IV, is responsible for cAMPbreakdown in airway smooth muscle and inflammatory cells. [Torphy,"Phosphodiesterase Isozymes: Potential Targets for Novel Anti-asthmaticAgents" in New Drugs for Asthma, Barnes, ed. IBC Technical ServicesLtd., 1989]. Research indicates that inhibition of this enzyme not onlyproduces airway smooth muscle relaxation, but also suppressesdegranulation of mast cells, basophils and neutrophils along withinhibiting the activation of monocytes and neutrophils. Moreover, thebeneficial effects of PDE IV inhibitors are markedly potentiated whenadenylate cyclase activity of target cells elevated by appropriatehormones or autocoids, as would be the case in vivo. Thus PDE IVinhibitors would be effective in the asthmatic lung, where levels ofprostaglandin E₂ and prostacyclin (activators of adenylate cyclase) areelevated. Such compounds would offer a unique approach toward thepharmacotherapy of bronchial asthma and possess significant therapeuticadvantages over agents currently on the market.

The compounds of this invention also inhibit the production of TumorNecrosis Factor (TNF), a serum glycoprotein. Excessive or unregulatedTNF production has been implicated in mediating or exacerbating a numberof diseases including rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, gouty arthritis and other arthritic conditions: sepsis,septic shock, endotoxic shock, gram negative sepsis, toxic shocksyndrome, adult respiratory distress syndrome, cerebral malaria, chronicpulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, boneresorption diseases, reperfusion injury, graft vs. host reaction,allograft rejections, fever and myalgias due to infection, such asinfluenza, cachexia secondary to infection or malignancy, cachexiasecondary to human acquired immune deficiency syndrome (AIDS), AIDS, ARC(AIDS related complex), keloid formation, scar tissue formation, Crohn'sdisease, ulcerative colitis, or pyresis, in addition to a number ofautoimmune diseases, such as multiple sclerosis, autoimmune diabetes andsystemic lupus erythematosis.

AIDS results from the infection of T lymphocytes with HumanImmunodeficiency Virus (HIV). At least three types or strains of HIVhave been identified, i.e., HIV-1, HIV-2 and HIV-3. As a consequence ofHIV infection, T-cell-mediated immunity is impaired and infectedindividuals manifest severe opportunistic infections and/or unusualneoplasms. HIV entry into the T lymphocyte requires T lymphocyteactivation. Viruses such as HIV-1 or HIV-2 infect T lymphocytes after Tcell activation and such virus protein expression and/or replication ismediated or maintained by such T cell activation. Once an activated Tlymphocyte is infected with HlV, the T lymphocyte must continue to bemaintained in an activated state to permit HIV gene expression and/orHIV replication.

Cytokines, specifically TNF, are implicated in activated T-cell-mediatedHIV protein expression and/or virus replication by playing a role inmaintaining T lymphocyte activation. Therefore, interference withcytokine activity such as by inhibition of cytokine production, notablyTNF, in an HIV-infected individual aids in limiting the maintenance of Tcell activation, thereby reducing the progression of HIV infectivity topreviously uninfected cells which results in a slowing or elimination ofthe progression of immune dysfunction caused by HIV infection.Monocytes, macrophages, and related cells, such as kupffer and glialcells, have also been implicated in maintenance of the HIV infection.These cells, like T cells, are targets for viral replication and thelevel of viral replication is dependent upon the activation state of thecells. [See Rosenberg et al., The Immunopathogenesis of HIV Infection.Advances in immunology, Vol. 57, 1989]: Monokines, such as TNF, havebeen shown to activate HIV replication in monocytes and/or macrophages[See Poli et al., Proc. Natl. Acad. Sci., 87:782-784, 1990], therefore,inhibition of monokine production or activity aids in limiting HIVprogression as stated above for T cells.

TNF has also been implicated in various roles with other viralinfections, such as the cytomegalovirus (CMV), influenza virus,adenovirus, and the herpes virus for similar reasons as those noted.

TNF is also associated with yeast and fungal infections. SpecificallyCandida albicans has been shown to induce TNF production in vitro inhuman monocytcs and natural killer cells. [See Riipi et at., Infectionand Immunity, 58(9):2750-54, 1990; and Jafari et al., Journal ofInfectious Diseases, 164:389-95, 1991. See also Wasan et al.,Antimicrobial Agents and Chemotherapy, 35, (10):2046-48, 1991; and Lukeet al., Journal of Infectious Diseases, 162:211-214,1990].

The ability to control the adverse effects of TNF is furthered by theuse of the compounds which inhibit TNF in mammals who are in need ofsuch use. There remains a need for compounds which are useful intreating TNF-mediated disease states which are exacerbated or caused bythe excessive and/or unregulated production of TNF.

SUMMARY OF THE INVENTION

This invention relates to the novel compounds of the Formula (I), asshown below, useful in the mediation or inhibition of the enzymaticactivity (or catalytic activity) of phosphodiesterase IV (PDE IV). Thenovel compounds of the Formula (I) also have Tumor Necrosis Factor (TNF)inhibitory activity.

This invention also relates to the pharmaceutical compositionscomprising a compound of the Formula (I) and a pharmaceuticallyacceptable carrier or diluent.

The invention also relates to a method of mediation or inhibition of theenzymatic activity (or catalytic activity) of PDE IV in mammals,including humans, which comprises administering to a mammal in needthereof an effective amount of a compound of the Formula (I), as shownbelow.

The invention further provides a method for the treatment of allergicand inflammatory disease which comprises administering to a mammal,including humans, in need thereof, an effective amount of a compound ofthe Formula (I).

The invention also provides a method for the treatment of asthma whichcomprises administering to a mammal, including humans, in need thereof,an effective amount of a compound of the Formula (I).

This invention also relates to a method of inhibiting TNF production ina mammal, including humans, which method comprises administering to amammal in need of such treatment, an effective TNF inhibiting amount ofa compound of the Formula (I). This method may be used for theprophylactic treatment or prevention of certain TNF mediated diseasestates amenable thereto.

This invention also relates to a method of treating a human afflictedwith a human immunodeficiency virus (HIV), which comprises administeringto such human an effective TNF inhibiting amount of a compound of theFormula (I).

The compounds of the Formula (I) are also useful in the treatment ofadditional viral infections, where such viruses are sensitive toupregulation by TNF or will elicit TNF production in vivo.

The compounds of the Formula (I) are also useful in the treatment ofyeast and fungal infections, where such yeast and fungi are sensitive toupregulation by TNF or will elicit TNF production in vivo.

The compounds of this invention are represented by Formula (I): ##STR2##wherein: R₁ is --(CR₄ R₅)_(n) C(O)O(CR₄ R₅)_(m) R₆, --(CR₄ R₅)_(n)C(O)NR₄ (CR₄ R₅)_(m) R₆, --(CR₄ R₅)_(n) O(CR₄ R₅)_(m) R₆, or --(CR₄R₅)_(r) R₆ wherein the alkyl moieties may be optionally substituted withone or more halogens;

m is 0 to 2;

n is 1 to 4;

r is 1 to 6;

R₄ and R₅ are independently selected from hydrogen or a C₁₋₂ alkyl;

R₆ is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxyC₁₋₃ alkyl, halo substituted aryloxy C₁₋₃ alkyl, indanyl, indenyl, C₇₋₁₁polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl,tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C₃₋₆cycloalkyl, or a C₄₋₆ cycloalkyl containing one or two unsaturatedbonds, wherein the cycloalkyl and heterocyclic moieties may beoptionally substituted by 1 to 3 methyl groups or one ethyl group;provided that:

a) when R₆ is hydroxyl, then m is 2; or

b) when R₆ is hydroxyl, then r is 2 to 6: or

c) when R₆ is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then m is 1 or 2; or

d) when R₆ is 2-tetrahydropyranyl, 2-tetrahydrothiopyranyl,2-tetrahydrofuranyl, or 2-tetrahydrothienyl, then r is 1 to 6;

e) when n is 1 and m is 0, then R₆ is other than H in --(CR₄ R₅)_(n)O(CR₄ R₅)_(m) R₆ ;

X is YR₂, halogen, nitro, NR₄ R₅, or formyl amine:

Y is O or S(O)_(m) ';

m' is 0, 1, or 2;

X2 is O or NR₈ ;

X3 is hydrogen or X;

X4 is ##STR3## X₅ is H, R₉, OR₈, CN, C(O)R₈, C(O)OR₈, C(O)NR₈ R₈, or NR₈R₈ ;

R₂ is independently selected from the group consisting of --CH₃ and--CH₂ CH₃ optionally substituted by 1 or more halogens;

s is 0 to 4;

R₃ is hydrogen, halogen, C₁₋₄ alkyl, CH₂ NHC(O)C(O)NH₂, halo-substitutedC₁₋₄ alkyl, --CH═CR_(8') R_(8'), cyclopropyl optionally substituted byR_(8'), CN, OR₈, CH₂ OR₈, NR₈ R₁₀, CH₂ NR₈ R₁₀, C(Z')H, C(O)OR₈, C(O)NR₈R₁₀, or C.tbd.CR_(8') ;

Z' is O, NR₉, NOR₈, NCN, C(-CN)₂, CR₈ CN, CR₈ NO₂, CR₈ C(O)OR₈, CR₈C(O)NR₈ R₈, C(-CN)NO₂, C(-CN)C(O)OR₉, or C(-CN)C(O)NR₈ R₈ ;

Z is C(Y')R₁₄, C(O)OR₁₄, C(Y')NR₁₀ R₁₄, C(NR₁₀)NR₁₀ R₁₄, CN, C(NOR₈)R₁₄,C(O)NR₈ NR₈ C(O)R₈, C(O)NR₈ NR₁₀ R₁₄, C(NOR₁₄)R₈, C(NR₈)NR₁₀ R₁₄, C(NR14)NR₈ R₈, C(NCN)NR₁₀ R₁₄, C(NCN)SR₉, (2-, 4-or 5-imidazolyl), (3-, 4-or 5-pyrazolyl), (4- or 5-triazolyl[1,2,3]), (3- or 5-triazolyl[1,2,4]),(5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or5-oxadiazolyl[1,2,4]), (2-oxadiazolyl[1,3,4]), (2-thiadiazolyl[1,3,4]),(2-, 4-, or 5-thiazolyl), (2-, 4-, or 5-oxazolidinyl), (2-, 4-, or5-thiazolidinyl), or (2-, 4-, or 5-imidazolidinyl); wherein all of theheterocylic ring systems may be optionally substituted one or more timesby R₁₄ ;

the dotted line in formula (a) represents a single or double bond:

Y' is O or S;

R₇ is --(CR₄ R₅)_(q) R₁₂ or C₁₋₆ alkyl wherein the R₁₂ or C₁₋₆ alkylgroup is optionally substituted one or more times by C₁₋₂ alkyloptionally substituted by one to three fluorines, --F, --Br, --Cl,--NO₂, --NR₁₀ R₁₁, --C(O)R₈, --C(O)OR₈, --OR₈, --CN, --C(O)NR₁₀ R₁₁,--OC(O)NR₁₀ R₁₁, --OC(O)R₈, --NR₁₀ C(O)NR₁₀ R₁₁, --NR₁₀ C(O)R₁₁, --NR₁₀C(O)OR₉, --NR₁₀ C(O)R₁₃, --C(NR₁₀)NR₁₀ R₁₁, --C(NCN)NR₁₀ R₁₁,--C(NCN)SR₉, --NR₁₀ C(NCN)SR₉, --NR₁₀ C(NCN)NR₁₀ R₁₁, --NR₁₀ S(O)₂ R₉,--S(O)m'R₉, --NR₁₀ C(O)C(O)NR₁₀ R₁₁, --NR₁₀ C(O)C(O)R₁₀, thiazolyl,imidazolyl, oxazolyl, pyrazolyl, triazolyl, or tetrazolyl;

q is 0, 1, or 2;

R₁₂ is C₃₋₇ cycloalkyl, (2-, 3- or 4-pyridyl), pyrimidyl, pyrazolyl, (1-or 2-imidazolyl), thiazolyl, triazolyl, pyrrolyl, piperazinyl,piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), (4- or5-thiazolyl), quinolinyl, naphthyl, or phenyl:

R₈ is independently selected from hydrogen or R₉ :

R_(8') is R₈ or fluorine:

R₉ is C₁₋₄ alkyl optionally substituted by one to three fluorines;

R₁₀ is OR₈ or R₁₁ ;

R₁₁ is hydrogen, or C₁₋₄ alkyl optionally substituted by one to threefluorines; or when R₁₀ and R₁₁ are as NR₁₀ R₁₁ they may together withthe nitrogen form a 5 to 7 membered ring optionally containing at leastone additional heteroatom selected from O/N/or S;

R₁₃ is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl,tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl,oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings isconnected through a carbon atom and each may be unsubstituted orsubstituted by one or two C₁₋₂ alkyl groups;

R₁₄ is hydrogen or R₇ ; or when R₁₀ and R₁₄ are as NR₁₀ R₁₄ they maytogether with the nitrogen form a 5 to 7 membered ring optionallycontaining one or more additional heteroatoms selected from O, N, or S;

provided that:

f) when R₁₂ is N-pyrazolyl, N-imidazolyl, N-triazolyl, N-pyrrolyl,N-piperazinyl, N-piperidinyl, or N-morpholinyl, then q is not 1; or

g) when X₂ R₁ is OCF₂ H or OCF₃, X is F, OCF₂ H or OCF₃, X₃ is H, s iszero, X₅ is H, Z is C(O)OR₁₄ and R₁₄ is C₁₋₇ unsubstituted alkyl, thenR₃ is other than H;

or the pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

This invention relates to the novel compounds of Formula (I), and topharmaceutical compositions comprising a compound of Formula (I) and apharmaceutically acceptable carrier or diluent. This invention alsorelates to a method of mediating or inhibiting the enzymatic activity(or catalytic activity) of PDE IV in a mammal in need thereof and toinhibiting the production of TNF in a mammal in need thereof, whichcomprises administering to said mammal an effective amount of a compoundof the Formula (I).

Phosphodiesterase IV inhibitors are useful in the treatment of a varietyof allergic and inflammatory diseases including: asthma, chronicbronchitis, atopic dermatitis, urticaria, allergic rhinitis, allergicconjunctivitis, vernal conjunctivitis, eosinophilic granuloma,psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis,Crohn's disease, reperfusion injury of the myocardium and brain, chronicglomerulonephritis, endotoxic shock and adult respiratory distresssyndrome. In addition, PDE IV inhibitors are useful in the treatment ofdiabetes insipidus, [Kidney Int., 37:362, 1990; Kidney Int., 35:494,1989] and central nervous system disorders such as depression andmulti-infarct dementia.

The compounds of the Formula (I) are also useful in the treatment ofviral infections, where such viruses are sensitive to upregulation byTNF or will elicit TNF production in vivo. The viruses contemplated fortreatment herein are those that produce TNF as a result of infection, orthose which are sensitive to inhibition, such as by decreasedreplication, directly or indirectly, by the TNF inhibitors of theFormula (I). Such viruses include, but are not limited to HIV-1, HIV-2and HIV-3, cytomegalovirus (CMV), influenza, adenovirus and the Herpesgroup of viruses, such as, but not limited to, Herpes zoster and Herpessimplex.

This invention more specifically relates to a method of treating amammal, afflicted with a human immunodeficiency virus (HIV), whichcomprises administering to such mammal an effective TNF inhibitingamount of a compound of the Formula (I).

The compounds of the Formula (I) may also be used in association withthe veterinary treatment of animals, other than in humans, in need ofinhibition of TNF production. TNF mediated diseases for treatment,therapeutically or prophylactically, in animals include disease statessuch as those noted above, but in particular viral infections. Examplesof such viruses include, but are not limited to feline immunodeficiencyvirus (FIV) or other retroviral infection such as equine infectiousanemia virus, caprine arthritis virus, visna virus, maedi virus andother lentiviruses.

The compounds of the Formula (I) are also useful in the treatment ofyeast and fungal infections, where such yeast and fungi are sensitive toupregulation by TNF or will elicit TNF production in vivo. A preferreddisease state for treatment is fungal meningitis. Additionally, thecompounds of the Formula (I) may be administered in conjunction withother drugs of choice for systemic yeast and fungal infections. Drugs ofchoice for fungal infections, include but are not limited to the classof compounds called the polymixins, such as Polymycin B, the class ofcompounds called the imidazoles, such as clotrimazole, econazole,miconazole, and ketoconazole; the class of compounds called thetriazoles, such as fluconazole, and itranazole, and the class ofcompound called the Amphotericins, in particular Amphotericin B andliposomal Amphotericin B.

The co-administration of the anti-fungal agent with a compound of theFormula (I) may be in any preferred composition for that compound suchas is well known to those skilled in the art, for instance the variousAmphotericin B formulations. Co-administration of an anti-fungal agentwith a compound of the Formula (I) may mean simultaneous administrationor in practice, separate administration of the agents to the mammal butin a consecutive manner. In particular, the compounds of the Formula (I)may be co-administered with a formulation of Amphotericin B, notably forsystemic fungal infections. The preferred organism for treatment is theCandida organism. The compounds of the Formula (I) may beco-administered in a similar manner with anti-viral or anti-bacterialagents.

The compounds of the Formula (I) may also be used for inhibiting and/orreducing the toxicity of an anti-fungal, anti-bacterial or anti-viralagent by administering an effective amount of a compound of the Formula(I) to a mammal in need of such treatment. Preferably, a compound of theFormula (I) is administered for inhibiting or reducing the toxicity ofthe Amphotericin class of compounds, in particular Amphotericin B.

When R₁ for the compounds of the Formula (I) is an alkyl substituted byI or more halogens, the halogens are preferably fluorine and chlorine,more preferably a C₁₋₄ alkyl substituted by I or more fluorines. Thepreferred halo-substituted alkyl chain length is one or two carbons, andmost preferred are the moieties --CF₃, --CH₂ F, --CHF₂, --CF₂ CHF₂,--CH₂ CH₃, and --CH₂ CHF₂. Preferred R₁ substitutents for the compoundsof the Formula (I) are CH₂ -cyclopropyl, CH₂ -C₅₋₆ cycloalkyl, C₄₋₆cycloalkyl, C₇₋₁₁ polycycloalkyl, (3- or 4-cyclopentenyl), phenyl,tetrahydrofuran-3-yl, benzyl or C₁₋₂ alkyl optionally substituted by 1or more fluorines, --(CH₂)₁₋₃ C(O)O(CH₂)₀₋₂ CH₃, --(CH₂)₁₋₃ O(CH₂) ₀₋₂CH₃, and --(CH₂)₂₋₄ OH.

When the R₁ term contains the moiety (CR₄ R₅), the R₄ and R₅ terms areindependently hydrogen or alkyl. This allows for branching of theindividual methylene units as (CR₄ R₅)_(n) or (CR₄ R₅)_(m) ; eachrepeating methylene unit is independent of the other, e.g., (CR₄ R₅)_(n)wherein n is 2 can be --CH₂ CH(--CH₃)--, for instance. The individualhydrogen atoms of the repeating methylene unit or the branchinghydrocarbon can optionally be substituted by fluorine independent ofeach other to yield, for instance, the preferred R₁ substitutions, asnoted above.

When R₁ is a C₇₋₁₁ polycycloalkyl, examples are bicyclo[2.2.1]-heptyl,bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, tricyclo[5.2.1.0²,6 ]decyl,etc. additional examples of which are described in Saccamano et at., WO87/06576, published 5 Nov. 1987, whose disclosure is incorporated hereinby reference in its entirety.

Z is preferably C(O)R₈, C(O)OR₈, C(O)NR₈ R₈, C(NR₈)NR₈ R₈, CN,C(NOR₈)R₈, C(O)NR₈ NR₈ C(O)R₈, C(NR₈)NR₈ R₈, C(NCN)NR₈ R₈, C(NCN)SR₉,(1-, 4- or 5-{R₈ }-2-imidazolyl), (1-, 4- or 5-{R₈ }-3-pyrazolyl), (1-,2- or 5-{R₈ }-4-triazolyl[1,2,3]), (1-, 2-, 4-or 5-{R₈}-3-triazolyl[1,2,4]), (1- or 2-{R₈ }-5-tetrazolyl), (4- or 5-{R₈}-2-oxazolyl), (3- or 4-{R₈ }-5-isoxazolyl), (3-{R₈}-5-oxadiazolyl[1,2,4]), (5-{R₈ }-3-oxadiazolyl[1,2,4]), (5-{R₈}-2-oxadiazolyl[1,3,4]), (5-{R₈ }-2-thiadiazolyl[1,3,4]), (4- or 5-{R₈}-2-thiazolyl), (4- or 5-{R₈ }-2-oxazolidinyl), (4- or 5-{R₈}-2-thiazolidinyl),(1-, 4- or 5-{R₈ }-2-imidazolidinyl); most preferredare those compounds wherein the R₈ group of Z is R₄.

X5 is preferably hydrogen, C₁₋₂ alkyl optionally substituted by one tothree fluorines, OR₈, CN, C(O)R₈, C(O)OR₈, C(O)NR₈ R₈, or NR₈ R₈.

Preferred X groups for Formula (I) are those wherein X is YR₂ and Y isoxygen. The preferred X₂ group for Formula (I) is that wherein X₂ isoxygen. The preferred X₃ group for Formula (I) is that wherein X₃ ishydrogen. Preferred R₂ groups, where applicable, are C₁₋₂ alkyloptionally substituted by 1 or more halogens. The halogen atoms arepreferably fluorine and chlorine, more preferably fluorine. Morepreferred R₂ groups are those wherein R₂ is methyl, or thefluoro-substituted alkyls, specifically a C₁₋₂ alkyl, such as a --CF₃,--CHF₂, or --CH₂ CHF₂ moiety. Most preferred are the --CHF₂ and --CH₃moieties.

Preferred R₃ moieties are C(O)NH₂, C.tbd.CR₈, CN, C(Z')H, CH₂ OH, CH₂ F,CH₂ H, and CH₃. More preferred are C.tbd.CH and CN. Z' is preferably Oor NOR₈.

Preferred R₇ moieties include optionally substituted --(CH₂)₁₋₂(cyclopropyl), --(CH₂)₀₋₂ (cyclobutyl), --(CH₂)₀₋₂ (cyclopentyl),--(CH₂)₀₋₂ (cyclohexyl), --(CH₂)₀₋₂ (2-, 3- or 4-pyridyl), --(CH₂)₁₋₂(2-imidazolyl), --(CH₂)2(4-morpholinyl), --(CH₂)₂ (4-piperazinyl),--(CH₂)₁₋₂ (2-thienyl), --(CH₂)₁₋₂ (4-thiazolyl), and --(CH₂)₀₋₂ phenyl;

Preferred rings when R₁₀ and R₁₁ in the moiety -NR₁₀ R₁₁ together withthe nitrogen to which they are attached form a 5 to 7 membered ringoptionally containing at least one additional heteroatom selected fromO/N/or S include, but are not limited to 1-imidazolyl,2-(R₈)-1-imidazolyl, 1-pyrazolyl, 3-(R₈)-1-pyrazolyl, 1-triazolyl,2-triazolyl, 5-(R₈)-1-thiazolyl, 5-(R₈)-2-triazolyl,5-(R₈)-1-tetrazolyl, 5-(R₈)-2-tetrazolyl, 1-tetrazolyl, 2-tetrazolyl,morpholinyl, piperazinyl, 4-(R₈)-1-piperazinyl, or pyrrolyl ring.

Preferred rings when R₁₀ and R₁₄ in the moiety -NR₁₀ R₁₄ together withthe nitrogen to which they are attached may form a 5 to 7 membered ringoptionally containing at least one additional heteroatom selected fromO, N, or S include, but are not limited to 1-imidazolyl, 1-pyrazolyl,1-triazolyl, 2-triazolyl, 1-tetrazolyl, 2-tetrazolyl, morpholinyl,piperazinyl, and pyrrolyl. The respective rings may be additionallysubstituted, where applicable, on an available nitrogen or carbon by themoiety R₇ as described herein for Formula (I). Illustrations of suchcarbon substitutions includes, but are not limited to,2-(R₇)-1-imidazolyl, 4-(R₇)-1-imidazolyl, 5-(R₇)-1-imidazolyl,3-(R₇)-1-pyrazolyl, 4-(R₇)-1-pyrazolyl, 5-(R₇)-1-pyrazolyl,4-(R₇)-2-triazolyl, 5-(R₇)-2-triazolyl, 4-(R₇)-1-triazolyl,5-(R₇)-1-triazolyl, 5-(R₇)-1-tetrazolyl, and 5-(R₇) -2-tetrazolyl.Applicable nitrogen substitution by R₇ includes, but is not limited to,1-(R₇)-2-tetrazolyl, 2-(R₇)-1-tetrazolyl, 4-(R₇)-1-piperazinyl. Whereapplicable, the ring may be substituted one or more times by R₇.

Preferred groups for NR₁₀ R₁₄ which contain a heterocyclic ring are5-(R₁₄)-1-tetrazolyl, 2-(R₁₄)-1-imidazolyl, 5-(R₁₄)-2-tetrazolyl, or4-(R₁₄)-1-piperazinyl.

Preferred rings for R₁₃ include (2-, 4- or 5-imidazolyl), (3-, 4- or5-pyrazolyl), (4- or 5-triazolyl[1,2,3]), (3- or 5-triazolyl[1,2,4]),(5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or5-oxadiazolyl[1,2,4]), (2-oxadiazolyl[1,3,4]), (2-thiadiazolyl[1,3,4]),(2-, 4-, or 5-thiazolyl), (2-, 4-, or 5-oxazolidinyl), (2-, , 4-, or5-thiazolidinyl), or (2-, 4- or 5-imidazolidinyl).

When the R₇ group is optionally substituted by a heterocyclic ring suchas imidazolyl, pyrazolyl, triazolyl, tetrazolyl, or thiazolyl, theheterocyclic ring itself may be optionally substituted by R₈ either onan available nitrogen or carbon atom, such as 1-(R₈)-2-imidazolyl,1-(R₈)-4-imidazolyl, 1-(R₈)-5-imidazolyl, 1-(R₈)-3-pyrazolyl,1-(R₈)-4-pyrazolyl, 1-(R₈)-5-pyrazolyl, 1-(R₈)-4-triazolyl, or 1-(R₈)-5-triazolyl. Where applicable, the ring may be substituted one or moretimes by R₈.

Preferred are those compounds of the Formula (I) wherein R₁ is --CH₂-cyclopropyl, --CH₂ -C₅₋₆ cycloalkyl, --C₄₋₆ cycloalkyl,tetrahydrofuran-3-yl, (3- or 4-cyclopentenyl), benzyl or --C₁₋₂ alkyloptionally substituted by 1 or more fluorines, and -(CH₂)₂₋₄ OH; R₂ ismethyl or fluoro-substituted alkyl, R₃ is CN or C.tbd.CR₈ ; and X isYR₂.

Most preferred are those compounds wherein R₁ is --CH₂ -cyclopropyl,cyclopentyl, methyl or CH₂ H; R₃ is CN or C.tbd.CH; X is YR₂ ; Y isoxygen; X₂ is oxygen; X₃ is hydrogen; and R₂ is CH₂ H or methyl.

A preferred subgenus of the compounds of the Formula (I) is thecompounds of the Formula (Ia) ##STR4## wherein: R₁ is CH₂ -cyclopropyl,CH₂ -C₅₋₆ cycloalkyl, C₄₋₆ cycloalkyl, C₇₋₁₁ polycycloalkyl, (3- or4-cyclopentenyl), phenyl, tetrahydrofuran-3-yl, benzyl or C₁₋₂ alkyloptionally substituted by 1 or more fluorines, --(CH₂)₁₋₃ C(O)O(CH₂)₀₋₂CH₃, --(CH₂)₁₋₃ O(CH₂)₀₋₂ CH₃, and --(CH₂)₂₋₄ OH;

X is YR₂, halogen, nitro, NR₄ R₅, or formyl amine;

X₄ is ##STR5## X₅ is H, R₉, OR₈, CN, C(O)R₈, C(O)OR₈, C(O)NR₈ R₈, or NR₈R₈ ;

Y is O or S(O)m';

m' is 0, 1, or 2;

R₂ is --CH₃ or --CH₂ CH₃ optionally substituted by 1 or more halogens;

R₃ is hydrogen, C₁₋₄ alkyl, CH₂ NHC(O)C(O)NH₂, halo-substituted C₁₋₄alkyl, CN, CH₂ OR₈, C(Z')H, C(O)OR₈, C(O)NR₈ R₁₀, or C.tbd.CR₈ ;

Z' is O or NOR₈ ;

Z is C(O)R₁₄, C(O)OR₁₄, C(O)NR₁₀ R₁₄, C(NR₁₀)NR₁₀ R₁₄, CN, C(NOR₈)R₁₄,C(O)NR₈ NR₈ C(O)R₈, C(O)NR₈ NR₁₀ R₁₄, C(NOR₁₄)R₈, C(NR₈)NR₁₀ R₁₄,C(NR₁₄)NR₈ R₈, C(NCN)NR₁₀ R₁₄, C(NCN)SR₉, (1-, 4- or 5-{R₁₄}-2-imidazolyl), (1-, 4- or 5-{R₁₄ }-3-pyrazolyl), (1-, 2- or 5-{R₁₄}-4-triazolyl[1,2,3]), (1-, 2, 4- or 5-{R₁₄ }-3-triazolyl[1,2,4]), (1-or 2-{R₁₄ }-5-tetrazolyl), (4- or 5-{R₁₄ }-2-oxazolyl), (3- or 4-{R₁₄}-5-isoxazolyl), (3-{R₁₄ }-5-oxadiazolyl[1,2,4]), (5-{R₁₄}-3-oxadiazolyl[1,2,4]), (5-{R₁₄ }-2-oxadiazolyl[1,3,4]), (5-{R₁₄}-2-thiadiazolyl[1,3,4]), (4- or 5-{R₁₄ }-2-thiazolyl), (4- or 5-{R₁₄}-2-oxazolidinyl), (4- or 5-{R₁₄ }-2-thiazolidinyl),(1-, 4- or 5-{R₁₄}-2-imidazolidinyl);

R₇ is --(CR₄ R₅)_(q) R₁₂ or C₁₋₆ alkyl wherein the R₁₂ or C₁₋₆ alkylgroup is optionally substituted one or more times by C₁₋₂ alkyloptionally substituted by one to three fluorines, --F, --Br, --Cl,--NO₂, --NR₁₀ R₁₁, --C(O)R₈, --C(O)OR₈, --OR₈, --CN, --C(O)NR₁₀ R₁₁,--OC(O)NR₁₀ R₁₁, --OC(O)R₈, --NR₁₀ C(O)NR₁₀ R₁₁, --NR₁₀ C(O)R₁₁, --NR₁₀C(O)OR₉, --NR₁₀ C(O)R₁₃, --C(NR₁₀)NR₁₀ R₁₁, --C(NCN)NR₁₀ R₁₁,--C(NCN)SR₉, --NR₁₀ C(NCN)SR₉, --NR₁₀ C(NCN)NR₁₀ R₁₁, --NR₁₀ S(O)₂ R₉,--S(O)m'R₉, --NR₁₀ C(O)C(O)NR₁₀ R₁₁, --NR₁₀ C(O)C(O)R₁₀, thiazolyl,imidazolyl, oxazolyl, pyrazolyl, triazolyl, or tetrazolyl;

q is 0, 1, or 2;

R₁₂ is C₃₋₇ cycloalkyl, (2-, 3- or 4-pyridyl), (1- or 2-imidazolyl),piperazinyl, morpholinyl, (2- or 3-thienyl), (4- or 5-thiazolyl), orphenyl;

the dotted line formula (a) represents a single or double bond:

R₈ is independently selected from hydrogen or R₉ ;

R₉ is C₁₋₄ alkyl optionally substituted by one to three fluorines;

R₁₀ is OR₈ or R₁₁ ;

R₁₁ is hydrogen or C₁₋₄ alkyl optionally substituted by one to threefluorines; or when R₁₀ and R₁₁ are as NR₁₀ R₁₁ they may together withthe nitrogen form a 5 to 7 membered ring optionally containing at leastone additional heteroatom selected from O/N/or S;

R₁₃ is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl,tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl,oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings isconnected through a carbon atom and each may be unsubstituted orsubstituted by one or two C₁₋₂ alkyl groups;

R₁₄ is hydrogen or R₇ ; or when R₁₀ and R₁₄ are as NR₁₀ R₁₄ they maytogether with the nitrogen form a 5 to 7 membered ring optionallycontaining one or more additional heteroatoms selected from O/N/or S;

provided that:

a) when R₁₂ is N-imidazolyl, N-triazolyl, N-pyrrolyl, N-piperazinyl, orN-morpholinyl, then q is not 1; or

b) when R₁ is CH₂ H or CH₃, X is F, OCH₂ H, or OCF₃, X₅ is H, Z isC(O)OR₁₄ and R₁₄ is C₁₋₇ unsubstituted alkyl, then R₃ is other than H;

or the pharmaceutically acceptable salts thereof. Exemplified compoundsof Formula (I) are:

methyl4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylate;

4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylicacid;

methylcis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-caxboxylate];

methyltrans-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate];

methylcis-{4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylate];

methyltrans-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylate];

cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid];

cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate],tris(hydroxymethyl)ammonium methane salt;

cis-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane1-carboxylicacid];

trans-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid];

cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid];

trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid];

methylcis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylate];

methyltrans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylate];

methyl cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-carboxylate];

methyltrans-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-carboxylate];

cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-carboxylicacid];

trans-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-carboxylicacid];

cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxamide];

cis-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane-1-carboxamide];

trans-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane-1-carboxamide];

cis-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane-1-carbohydrazide];

cis-[4-cyano-4-(3,4-bisdifluoromethoxyphenyl)cyclohexane-1-(2-acetylcarbohydrazide)];

cis-{4-(3,4-bisdifluoromethoxyphenyl)-4-cyano-1-(3-methyl[1,2,4]oxadiazol-5-yl)cyclohexane};

cis-{4-(3,4-bisdifluoromethoxyphenyl)-4-cyano-1-(2-methyl[1,3,4]oxadiazol-5-yl)cyclohexane};

cis-{4-(3,4-bisdifluoromethoxyphenyl)-4-cyano-1-(2-methyl[1,3,4]thiadiazol-5-yl)cyclohexane};

cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxy-1-tris(methylthio)methylcyclohexane];

methylcis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylate];

cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylicacid];

cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxamide];

methylcis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxylate];

cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxylicacid];

cis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxamide];

trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxaldehyde];

methyltrans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylate]

trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylicacid];

methyltrans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxylate]

trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxylicacid];

trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxamide];

cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxamicacid];

N-methyl-cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxamicacid];

cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-N-(2-cyanoethyl)carboxamide];

cis-[1-(2-cyanoethyl)-5-{4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexyl}tetrazole];and

cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-1-(tetrazol-5-yl)cyclohexane].

Some compounds of Formula (I) may exist in both racemic and opticallyactive forms: some may also exist in distinct diastereomeric formspossessing distinct physical and biological properties. All of thesecompounds are considered to be within the scope of the presentinvention. Therefore another aspect of the present invention is theadministration of either a racemate, a single enantiomeric form, asingle diastereomeric form, or mixtures thereof.

The terms cis and trans denote stereochemistry at the C-1 position ofthe cyclohexane ring relative to the R₃ group at the C-4 position.

The terms "C₁₋₃ alkyl", "C₁₋₄ alkyl", "C₁₋₆ alkyl" or "alkyl" includeboth straight or branched chain radicals of 1 to 10, unless the chainlength is limited thereto, including, but not limited to methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, and thelike. "Alkenyl" includes both straight or branched chain radicals of 1to 6 carbon lengths, unless the chain length is limited thereto,including but not limited to vinyl, 1-propenyl, 2-propenyl, 2-propynyl,or 3-methyl-2-propenyl. "Cycloalkyl" or "cycloalkyl alkyl" includesgroups of 3-7 carbon atoms, such as cyclopropyl, cyclopropylmethyl,cyclopentyl, or cyclohexyl. "Aryl" or "aralkyl", unless specifiedotherwise, means an aromatic ring or ring system of 6-10 carbon atoms,such as phenyl, benzyl, phenethyl, or naphthyl. Preferably the awl ismonocyclic, i.e, phenyl. The alkyl chain includes both straight orbranched chain radicals of 1 to 4 carbon atoms. "Heteroaryl" as usedherein, is meant an aromatic ring system containing one or moreheteroatoms, such as imidazolyl, triazolyl, oxazolyl, pyridyl,pyrimidyl, pyrazolyl, pyrrolyl, furanyl, or thienyl. "Halo" as usedherein is meant all halogens, i.e., chloro, fluoro, bromo, or iodo.

The phrase "inhibiting the production of IL-1" or "inhibiting theproduction of TNF" means:

a) a decrease of excessive in vivo IL-1 or TNF levels, respectively, ina human to normal levels or below normal levels by inhibition of the invivo release of IL-1 by all cells, including but not limited tomonocytes or macrophages;

b) a down regulation, at the translational or transcriptional level, ofexcessive in vivo IL-1 or TNF levels, respectively, in a human to normallevels or below normal levels; or

c) a down regulation, by inhibition of the direct synthesis of IL-1 orTNF levels as a postranslational event.

"TNF mediated disease or disease states" means any and all diseasestates in which TNF plays a role, either by production of TNF itself, orby TNF causing another cytokine to be released, such as but not limitedto IL-1 or IL-6. A disease state in which IL-1, for instance is a majorcomponent, and whose production or action, is exacerbated or secreted inresponse to TNF, would therefore be considered a disease state mediatedby TNF. As TNF-β (also known as lymphotoxin) has close structuralhomology with TNF-α (also known as cachectin), and since each inducessimilar biologic responses and binds to the same cellular receptor, bothTNF-α and TNF-β are inhibited by the compounds of the present inventionand thus are herein referred to collectively as "TNF" unlessspecifically delineated otherwise. Preferably TNF-α is inhibited.

"Cytokine" means any secreted polypeptide that affects the functions ofcells, and is a molecule which modulates interactions between cells inimmune, inflammatory, or hematopoietic responses. A cytokine includes,but is not limited to, monokines and lymphokines regardless of whichcells produce them. For instance, a monokine is generally referred to asbeing produced and secreted by a mononuclear cell, such as a macrophageand/or monocyte, but many other cells produce monokines, such as naturalkiller cells, fibroblasts, basophils, neutrophils, endothelial cells,brain astrocytes, bone marrow stromal cells, epidermal keratinocytes,and B-lymphocytes. Lymphokines are generally referred to as beingproduced by lymphocyte cells. Examples of cytokines for the presentinvention include, but are not limited to, Interleukin-1 (IL-1),Interleukin-6 (IL-6), Interleukin-8 (IL-8 Tumor Necrosis Factor-alpha(TNF-α) and Tumor Necrosis Factor-beta (TNF-β).

The cytokine inhibited by the present invention for use in the treatmentof a HIV-infected human must be a cytokine which is implicated in (a)the initiation and/or maintenance of T cell activation and/or activatedT cell-mediated HIV gene expression and/or replication, and/or (b) anycytokine-mediated disease associated problem such as cachexia or muscledegeneration. Preferably this cytokine is TNF-α.

All of the compounds of Formula (I) are useful in the method ofinhibiting the production of TNF, preferably by macrophages, monocytesor macrophages and monocytes, in a mammal, including humans, in needthereof. All of the compounds of Formula (I) are useful in the method ofinhibiting or mediating the enzymatic or catalytic activity of PDE IVand in treatment of disease states mediated thereby.

METHODS OF PREPARATION:

Preparing compounds of the Formula (I) can be carried out by one ofskill in the art according to the procedures outlined in the Examples,infra. The preparation of any remaining compounds of the Formula (I) notdescribed therein may be prepared by the analogous processes disclosedherein which comprise:

a) for compounds of the Formula (I) wherein R₃ is H, CN, OR₉, C₁₋₄ alkylor C₁₋₄ halosubstituted alkyl, wherein X or X₃ is other than Br, I, NO₂,amino, formyl amine or S(O)m' when m' is 1 or 2, wherein Z is CHO andthe double bond is present, reacting a compound of the Formula (2)##STR6## wherein R₁ represents R₁ as defined in relation to Formula (I)or a group convertable to R₁ and X and X₃ represent X and X₃ as definedin relation to Formula (I) or a group convertable to X or X₃ and R₃represents R₃ as defined in relation to Formula (I) or a groupconvertable to R₃, with nitromethane in a suitable non-reacting solventin the presence of a base (catalyst 1 to provide compounds of theFormula (I) wherein R₃ is H, CN, OR₉, C₁₋₄ alkyl or C₁₋₄ halosubstitutedalkyl, wherein X and X₃ are other than Br, I, NO₂, amino, formyl amineor S(O)m' when m' is 1 or 2, wherein Z is CH₂ NO₂ and the double bond ispresent; treatment of such compounds with a base, such as sodiummethoxide, in the presence of, e.g., buffered titanium trichloride,provides compounds of the Formula (I) wherein R₃ is H, CN, OR₉, C₁₋₄alkyl or C₁₋₄ halosubstituted alkyl, wherein X or X₃ are other than Br,I, NO₂, amino, formyl amine or S(O)m' when m' is 1 or 2 and wherein Z isCHO and the double bond is present. Double bond reduction of suchcompounds of the Formula (I) provides the corresponding saturated ringFormula (I) compounds; oxidation of the aldehyde function of eitherthese saturated or unsaturated compounds of the Formula (I) provides thecorresponding Formula (I) carboxylates (Z=COOH), which may be convenedby standard procedures with proper manipulation of any chemicallysensitive functional groups to the corresponding ester, amide, nitrile,oxazolidinone, etc., Z groups of the Formula (I).

Alternatively, reaction of a compound of the Formula (2) with, e.g.,tosylmethyl isocyanide and potassium t-butoxide (followed by hydrolysis)or lithium methoxyphenylthiotrimethylsilylmethane (followed byhydrolysis) provides compounds of the Formula (I) wherein R₃ is H, CN,OR₉, C₁₋₄ alkyl or C₁₋₄ halosubstituted alkyl, wherein X and X₃ areother than Br, I, NO₂, amino, formyl amine or S(O)m' when m' is 1 or 2,wherein Z is CO₂ R₁₅, the double bond is present, and R₁₅ is H or simplealkyl; these then may be converted by standard procedures with propermanipulation (protection/deprotection) of any chemically sensitivefunctional groups to the corresponding ester, amide, nitrile,oxazolidinone, etc., Z groups of the Formula (I).

Alternatively, reaction of a compound of the Formula (2) with, e.g.,triflic anhydride in the presence of an appropriate tertiary amine base,or with an alkyl lithium at a reduced temperature followed by treatmentwith N-phenyl trifluorosulfonimide, provides the corresponding enoltriflate, which is then reacted with carbon monoxide in the presence ofan alcohol or amine and an appropriate palladium catalyst to providecompounds of the Formula (I) wherein R₃ is H, CN, OR₉, C₁₋₄ alkyl orC₁₋₄ halosubstituted alkyl, wherein X and X₃ are other than Br, I, NO₂,amino, formyl amine or S(O)m' when m' is 1 or 2, wherein Z is CO₂ R₁₅ orCONR₁₀ R₁₄, the double bond is present, and R₁₅ is H or simple alkyl;these then may be converted by standard procedures with propermanipulation (protection/deprotection) of any chemically sensitivefunctional groups to the corresponding ester, amide, nitrile,oxazolidinone, etc., Z groups of the Formula (I).

Alternatively, reaction of a compound of the Formula (2) with, e.g.,lithium tris(methylthio)_(m) ethane at reduced temperature, followed bymercury, salt hydrolysis and alcohol treatment provides compounds of theFormula (I) wherein R₃ is H, CN, OR₉, C₁₋₄ alkyl or C₁₋₄ halosubstitutedalkyl, wherein X and X₃ are other than Br, I, NO₂, amino, formyl amineor S(O)m' when m' is 1 or 2, wherein Z is CO₂ R₁₅ and X₅ is OH, thedouble bond is absent, and R₁₅ is H or simple alkyl. Such compounds mayalso be obtained by reaction of a compound of the Formula (2) withtrimethylsulfoxonium iodide or trimethylsulfonium iodide and anappropriate base, such as sodium hydride, to provide the exo-epoxidefollowed by treatment with aqueous potassium hydroxide in, e.g.,dimethylsulfoxide and oxidation of the resulting primary alcohol to thecarboxyl provides compounds of the Formula (I) wherein R₃ is H, CN, OR₉,C₁₋₄ alkyl or C₁₋₄ halosubstituted alkyl, wherein X and X₃ are otherthan Br, I, NO₂, amino, formyl amine or S(O)m' when m' is 1 or 2,wherein Z is CO₂ R₁₅ and X₅ is OH, the double bond is absent, and R₁₅ isH or simple alkyl; the R₅ hydroxyl may be alkylated and these compoundsthen may be convened by standard procedures with proper manipulation(protection/deprotection) of any chemically sensitive functional groupsto the corresponding ester, amide, nitrile, oxazolidinone, etc., Zgroups of the Formula (I).

Alternatively, reaction of a compound of the Formula (2) with, e.g.,2-lithio-2-(trimethylsilyl)-1,3-dithiane followed by acidic hydrolysiswith a mercury salt, such as mercury (II) chloride, or reaction of acompound of the Formula (2) with, e.g., sodio-[diethylt-butoxy(cyano)_(m) ethyl phosphonate] followed by treatment with aceticanhydride and a zinc halide and then followed by treatment with analkoxide provides compounds of the Formula (I) wherein R₃ is H, CN, OR₉,C₁₋₄ alkyl or C₁₋₄ halosubstituted alkyl, wherein X and X₃ are otherthan Br, I, NO₂, amino, formyl amine or S(O)m' when m' is 1 or 2,wherein Z is CO₂ R₁₅, the double bond is not present, and R₁₅ is H orsimple alkyl and R₅ is H; these then may be converted by standardprocedures with proper manipulation (protection/deprotection) of anychemically sensitive functional groups to the corresponding ester,amide, nitrile, oxazolidinone, etc., Z groups of the Formula (I).

Preparation of such compounds of the Formula (I) wherein R₃ is C(═Z')Hproceed in an analogous fashion from the compound of the Formula (2)wherein ═Z' is an aldehyde protecting group, such as a dimethylacetal ora dioxolane, followed by aldehyde deprotection and subsequentmanipulation by standard procedures known to those of skill in the an tothe remaining compounds of the Formula (I) wherein Z' is other than O orR₃ is other than H, CN, OR₉, C₁₋₄ alkyl or C₁₋₄ halosubstituted alkyl.

With proper manipulation (protection/deprotection) of any chemicallysensitive functional groups:

a) Compounds of the Formula (I) wherein X or X₃ are formyl amine may beformed at the last step, by formulating a compound wherein X or X₃ isNH₂, obtained by removal of a protecting group from the aminefunctionality; such protective groups are well known to those skilled inthe art, See Greene, T. and Wuts, P. G. M., Protecting Groups in OrganicSynthesis, 2nd Ed., John Wiley and Sons, New York (1991).

c) Compounds of the Formula (I) wherein X or X₃ are Br or I may beprepared from a similarly deprotected amine by diazotization of theamine and diazonium displacement.

d) Compounds of the Formula (I) wherein X or X₃ are NO₂ may be preparedfrom a similarly deprotected amine by oxidation of the amine to thenitro group.

e) Compounds of the Formula (I) wherein Y is S(O)m' when m' is I or 2may be prepared from the compounds of the Formula (I) wherein Y is S byoxidation of the SR₂ moiety under conditions well known those skilled inthe art

Compounds of the Formula (2) may be prepared in turn by the processesdescribed in co-pending application U.S. Ser. No. 07/862,083 filed 2Apr. 1992 and the corresponding continuation-in-pan application filed oneven date herewith.

It will be recognized that compounds of the Formula (I) may exist in twodistinct diastereomeric forms possessing distinct physical andbiological properties; such isomers may be separated by standardchromatographic methods.

The following examples and methods are provided to illustrate how themake and use the invention. These materials are not intended to limitthe invention in any manner; please refer to the claims appended heretofor determining what has been reserved to the inventors hereunder.

SYNTHETIC EXAMPLES EXAMPLE 1 Methyl4-cyano-4(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylate

4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-1-cyclohexenyltrifluoromethylsulfonate

To a solution of diisopropylamine[1.95 milliliters (hereinafter mL),13.9 millimoles (hereinafter mmol)] in tetrahydrofuran (12 mL) at 0° C.under an argon atmosphere was added n-butyllithium (5.8 mL of 2.5Msolution, 14.15 mmol), the resulting solution was stirred for 25 minutes(hereinafter min) and then was cooled to -78° C. To this was added asolution of 4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one[2 grams (hereinafter g), 6.64 mmol] in tetrahydrofuran (9 mL). Theresulting mixture was stirred at -78° C. for 2 hours (hereinafter h), atwhich time N-phenyl-trifluoromethylsulfonimide (4.98 g, 13.9 mmol) wasadded. The mixture was allowed to warm slowly to room temperature andafter 5 h, the mixture was poured into water and extracted withmethylene chloride. The organic extract was dried (potassium carbonate)and concentrated under reduced pressure. The residue was purified byflash chromatography, eluting with 4:1 hexanes/ethyl acetate, to affordan oil (1.09 g, 37%).

Methyl4-cyano4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylate

To a solution of4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-1-cyclohexenyltrifluoromethylsulfonate (1.0 g, 2.24 mmol) in 1:1methanol/N,N-dimethylformamide (8 mL) were added methylamine (0.66 mL,4.72 mmol) and tetrakis(triphenylphosphine)palladium (0.13 g, 0.11mmol). The resulting mixture was stirred at room temperature in the darkunder a carbon monoxide atmosphere for 3 h. The mixture was partitionedbetween water and ethyl acetate, the organic extract was washed threetimes with water, once with brine, was dried (potassium carbonate) andwas evaporated. Purification by flash chromatography, eluting with 3:1hexanes/ethyl acetate, provided an off-white solid (0.64 g, 80%): m.p.128°-129° C.

Analysis Calc. for C₂₁ H₂₅ NO₄.1/8 H₂ O: C 70.52, H 7.12, N 3.92; found:C 70.45, H 6.93, N 3.87.

EXAMPLE 24-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylicacid

To a solution of methyl4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylate(0.07 g, 0.18 mmol) in methanol (0.5 mL, containing just enoughtetrahydrofuran to solubilize the ester) under an argon atmosphere wasadded a solution of potassium hydroxide (0.03 g, 0.55 mmol) in water(0.4 mL). The resulting mixture was stirred at room temperature for 4 h,then poured into water and extracted with ethyl acetate. The aqueousphase was acidified with 3N hydrochloric acid and extracted twice withethyl acetate. The organic phase from the acid extraction was dried(sodium sulfate) and concentrated under reduced pressure to provide aviscous oil, which solidified upon standing. The solid wasrecrystallized from hexanes/methylene chloride (0.05 g, 82%): m.p.161°-163° C.

Analysis Calc. for C₂₀ H₂₃ NO₄.1/2H₂ O: C 68.55, H 6.90, N 4.00; found:C 68.65, H 6.55, N 3.82.

EXAMPLE 3 Methyl cis- andtrans-[4-cyano4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate]

Procedure 3A:

To a solution of methyl4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohex-1-ene-1-carboxylate(0.26 g, 0.73 mmol) in methanol (12 mL) was added 10% palladium onactivated carbon (0.15 g) and the resulting mixture was hydrogenated at50 psi for 5 h. The mixture was filtered through a pad of Celite andconcentrated under reduced pressure. The residue was partitioned betweenmethylene chloride and water, the extract was dried (potassiumcarbonate) and evaporated to a solid which was primarily the cis-ester(0.14 g, 54%): m.p. 94°-95° C.

Analysis Calc. for C₂₁ H₂₇ NO₄.1/8 H₂ O: C 70.32, H 7.38, N 3.90; found:C 70.33, H 7.59, N 3.81.

Procedure 3B:

2-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexylidene]-1,3-dithiane

To a solution of 2-trimethylsilyl-1,3-dithiane (9.25 mL, 48.7 mmol) indry-tetrahydrofuran (80 mL) at 0° C. under an argon atmosphere was addedrapidly n-butyllithium (2.5M in hexanes, 19.2 mL, 48 mmol). After 10min, the mixture was cooled to -78° C. and a solution of4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one (7.53 g, 23mmol) in tetrahydrofuran (40 mL) was added. After 10 min, aqueous sodiumchloride was added, the mixture was allowed to warm to room temperatureand was diluted with water. This mixture was combined with the productof three substantially similar reactions conducted on ketone (3.04, 6.01and 6.1 g, 48.3 mmol total), the combined mixture was extracted threetimes with methylene chloride, the extract was dried (magnesium sulfate)and evaporated. Purification by flash chromatography, eluting with 10%ethyl acetate/hexanes, provided a white solid (26 g, 87%): m.p.115°-116° C.

Methylcis-[4-Cyano-4-(3cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate]

Perchloric acid (70%, 13.8 mL, 160 mmol) and mercuric chloride (34.1 g,126 mmol) were added to a solution of2-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexylidene]-1,3-dithiane(13 g, 31.3 mmol) in methanol (0.5 L) under an argon atmosphere and themixture was heated at reflux for 2 h and then was allowed to stir atroom temperature for 42 h. The mixture was diluted with methylenechloride, was filtered through Celite and the filtrate was combined withthat of a similar reaction conducted concurrently on the same scale. Themixture was neutralized with aqueous sodium bicarbonate, was extractedthree times with methylene chloride, the organic extract was washedthree times with aqueous sodium sulfite, was dried (magnesium sulfate)and was evaporated. Purification by flash chromatography, eluting with15% ethyl acetate/hexanes, provided the cis-ester as a white solid (12.4g, 56%): m.p. 119°-120° C., along with an additional quantity ofslightly impure product (2.6 g, 12%).

Methyltrans-[4-Cyano-4-(3-cyclopentyloxy-4-cyanocyclohexylidene]-2-tert-butyloxy

The trans-ester was also isolated from this mixture as a solid (1.04 g,5%): m.p. 50°-51° C.

Analysis Calc. for C₂₁ H₂₇ NO₄.3/4 H₂ O: C 67.99, H 7.74, N 3.78; found:C 67.98, H 7.35, N 3.65.

EXAMPLE 4

Methyl cis andtrans-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylate]

Procedure 4A:

2-4(3,4-Bisdifluoromethoxyphenyl)-4-cyanocyclohexylidene]-2-tert-butyloxyacetonitrile

Sodium hydride (80% dispersion, 0.35 g, 11.7 mmol) was washed threetimes with pentane, was suspended in tetrahydrofuran (15 mL) at roomtemperature under an argon atmosphere and diethyltert-butyl(cyano)methylphosphonate (2.66 g, 10.7 mmol) was added. After0.5 h, a solution of4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexan-1-one (1.77 g, 5.34mmol) in tetrahydrofuran (5 mL) was added and the mixture was heated atreflux for 0.5 h. The mixture was cooled, aqueous sodium chloride andwater were added, the mixture was extracted three times with ether, theextract was dried (magnesium sulfate) and evaporated. Purification byflash chromatography, eluting with 20% ethyl acetate/hexanes, providedthe title compound as a white solid (1.18 g, 52%).

Methyl cis- andtrans-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylate

A mixture of2-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexylidene]-2-tert-butyloxyacetonitrile (0.25 g, 0.59 mmol) and zinc chloride (0.1 g, 0.7 mmol) inacetic anhydride (1.5 mL) under an argon atmosphere was heated at refluxfor 10 min, was cooled, was diluted with water and was extracted threetimes with ether. The organic extract was washed with water, dried(magnesium sulfate) and evaporated. A solution of this acetate inmethanol (6 mL) was treated with a solution of sodium methoxide (25% inmethanol, 0.17 mL, 0.71 mmol) and the mixture was stirred under an argonatmosphere for 2 h. The mixture was acidified with hydrochloric acid(1N), water was added and the mixture was extracted three times withmethylene chloride. The organic extract was dried (magnesium sulfate)and evaporated. Purification by flash chromatography and eluting with20% ethyl acetate/hexanes provided the trans-isomer as a colorless oil(0.07 g, 30%).

Analysis Calc. for C₁₇ H₁₇ F₄ NO_(4:) C 54.40, H 4.57, N 3.73; found: C54.57, H 4.51, N 3.58. The cis-isomer was also isolated as a yellow oil(0.1 g, 47%).

Procedure 4B:

Methylcis-14-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylate]

A solution ofcis-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylicacid (EXAMPLE 10, 0.07 g, 0.19 mmol) and trimethylsilyl chloride (0.12mL, 0.95 mmol) in methanol (5 mL) was stirred at room temperature underan argon atmosphere for 24 h. The solvent was evaporated and the residuewas purified by flash chromatography, eluting with 15% ethylacetate/hexanes, provided a colorless oil (0.05 g, 63%).

Analysis Calc. for C₁₇ H₁₇ F₄ NO_(4:) C 54.40, H 4.57, N 3.73; found: C54.45, H 4.49, N 3.42.

EXAMPLE 5cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid] andcis-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylicacid]

To a solution of methylcis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate](0.1 g, 0.34 mmol) in methanol (0.9 mL, containing just enoughtetrahydrofuran to solubilize the ester) under an argon atmosphere wasadded a solution of potassium hydroxide (0.06 g, 0.9 mmol) in water (0.7mL). The resulting mixture was stirred at room temperature for 1.5 h,then poured into water and extracted with ethyl acetate. The aqueousphase was acidified with 10% hydrochloric acid and extracted twice withethyl acetate. The organic phase from the acid extraction was dried(sodium sulfate) and concentrated under reduced pressure to provide asolid. The solid was purified by flash chromatography, eluting-with 4%methanol/chloroform, to provide a white solid (0.05 g, 44%): m.p. 157°C.

Analysis Calc. for C₂₀ H₂₅ NO₄.1/8H₂ O: C 68.75, H 7.40, N 4.01; found:C 68.74, H 7.08, N 3.84.

In a similar manner there was prepared:

cis-[4-(3,4-Bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylicacid] as a solid: m.p. 143°-144° C.

Analysis Calc. for C₁₆ H₁₅ F₄ NO₄ : C 53.19, H 4.18, N 3.88; found: C53.57, H 3.91, N 3.59.

EXAMPLE 6cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate],tris(hydroxymethyl)ammonium methane salt

To a solution ofcis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid](0.17 g, 0.5 mmol) in methanol (2 mL) was added an aqueous solutionof tris(hydroxymethyl)aminomethane (1.0M, 0.5 mL). After 10 min. thesolvent was evaporated, toluene and methanol were added and the liquidswere removed in vacuo. Trituration with ether provided a white solid(0.18 g, 79%): m.p. 191°-194° C.

Analysis Calc. for C₂₄ H₃₆ N₂ O₇.2.5H₂ O: C 56.57, H 8.11, N 5.50:found: C 56.44, H 7.75, N 5.62.

EXAMPLE 7 trans-[4-Cyano-4,(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid]

To a solution of methyltrans-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate](0.68 g, 1.9 mmol) in methanol (8 mL, containing just enoughtetrahydrofuran to solubilize the ester) under an argon atmosphere wasadded water (4 mL) and potassium hydroxide (0.32 g, 5.7 mmol). Theresulting mixture was stirred at room temperature for 24 h, wasacidified with 10% hydrochloric acid and was extracted three times with10% methanol/methylene chloride. The organic extract was dried(magnesium sulfate) and concentrated under reduced pressure.Purification by flash chromatography, eluting with 4% methanol/methylenechloride, provided a white semi-solid (0.52 g, 80%), which wastriturated with ether to yield a white solid (0.43 g): m.p. 157°-158° C.

Analysis Calc. for C₂₀ H₂₅ NO₄ : C 69.95, H 7.34, N 4.08; found: C69.69, H 7.30, N 4.07.

EXAMPLE 8 cis- andtrans-[4-Cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid]

8A.2-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexylidine]-2-tert-butyloxyacetonitrile

This compound, prepared substantially as described above for2-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclo-hexylidene]-2-tert-butyloxyacetonitrile in Procedure A of EXAMPLE 4, was isolated as a white solid:m.p. 109°-110° C.

8B. Methyl cis- andtrans-[4-cyano-4-(3-hydroxy-4-methoxyphenyl)cyclohexane-1-carboxylate]

These compounds, prepared substantially as described above for methylcis- andtrans-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylate]in Procedure A of EXAMPLE 4, were isolated as solids [cis-isomer (0.35g, 33%): m.p. 105°-106° C; trans-isomer (0.52 g, 49%): m.p. 103°-104°C.].

8C. Methylcis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylate]

A suspension of methylcis-[4-(3-hydroxy-4-methoxyphenyl)cyclohexane-1-carboxylate](0.35 g,1.20 mmol), powdered potassium carbonate (0.5 g, 3.6 mmol) andbromomethyl cyclopropane (0.35 mL, 3.6 mmol) in dry dimethylformamide(15 mL) under an argon atmosphere was heated at 85° C. for 4 h. Themixture was cooled, was diluted with water and was extracted three timeswith ether. The organic extract was washed four times with water, oncewith brine, was dried (potassium carbonate) and was evaporated.Purification by flash chromatography, eluting with 20% ethylacetate/hexanes, provided an oil (0.34 g, 82%).

8D.cis-[4-Cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid]

The title compound, prepared substantially as described above forcis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid] in EXAMPLE 7, was isolated as a solid: m.p. 165°-167° C.

Analysis Calc. for C₁₉ H₂₃ NO₄.1/5H₂ O: C 68.53, H 7.08, N 4.21; found:C 68.70, H 7.07, N 4.16.

8E. Methyltrans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxyate]

The title compound, prepared substantially as described above for methylcis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxyate]inEXAMPLE 8C was isolated as a solid: m.p. 27.5°-128° C.

Analysis Calc. for C₂₀ H₂₅ NO₄.3/8 H₂ O: C 68.60, H 7.41, N 4.00; found:C 68.50, H 7.28, N 3.88.

8F.trans-[4-Cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid]

The title compound, prepared substantially as described above forcis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid]in EXAMPLE 7, was isolated as a solid: m.p. 148° C.

Analysis Calc. for C₁₉ H₂₃ NO₄ : C 69.28, H 7.04, N 4.25; found: C68.97, H 7.03, N 4.25.

EXAMPLE 9 cis- andtrans-[4-Cyano-4-(3cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-carboxylicacid]

9A.2-[4-Cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexylidene]-1,3-dithiane

This compound, prepared substantially as described above for2-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexylidene]-1,3-dithianein Procedure B of EXAMPLE 3, was isolated as a solid: m.p. 84°-85° C.

9B. Methyl cis- andtrans-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-carboxylate]

These compounds, prepared substantially as described above for methylcis- andtrans-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate]in Procedure B of EXAMPLE 3, were isolated as oils.

9C.cis-[4-Cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-carboxylicacid

This compound, prepared substantially as described above forcis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid] in EXAMPLE 7, was isolated as a solid: m.p. 134°-135° C.

Analysis Calc. for C₁₉ H₂₁ F₂ NO₄ : C 62.46, H 5.79, N 3.83; found: C62.15, H 5.83, N 3.88.

9D.trans-[4-Cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-carboxylicacid

The title compound, prepared substantially as described above forcis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid] in EXAMPLE 7, was isolated as a solid: m.p. 128°-129° C.

EXAMPLE 10cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxamide]

To a solution of methylcis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylate](0.22 g, 0.62 mmol) and formamide (0.08 mL, 2.08 mmol) at 100° C. indimethylformamide (2 mL) under an argon atmosphere was added portionwiseover 20 min sodium methoxide (25% solution in methanol, 0.1 mL, 0.43mmol). After an additional 1.25 h at 100° C., the mixture was cooled,was poured into isopropanol, was filtered and the filtrate evaporated.The residue was dissolved in ethyl acetate, the organic phase was washedthree times with water, was dried (magnesium sulfate) and wasconcentrated under reduced pressure. Purification by flashchromatography, eluting with 3% methanol/methylene chloride, provided awhite foam (0.06 g, 28%).

Analysis Calc. for C₂₀ H₂₆ N₂ O₃.3/8 H₂ O: C 68.79, H 7.72, N 8.02;found: C 68.86, H 7.49, N 7.93.

EXAMPLE 11 cis-{4-(3,4,Bisdifluoromethoxyphenyl)-4-cyano-1-(3-methyl[1,2,4]oxadiazol-5-yl)cyclohexane]

cis-andtrans-[4-(3,4-Bisdifluoromethoxyphenyl),4-cyanocyclohexane-1-carboxamide]

These compounds, prepared substantially as described above forcis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxamide]in EXAMPLE 14, were isolated as a solid (cis isomer: m.p. 109°-110° C.)and as an oil (trans isomer).

cis-{4-(3,4-Bisdifluoromethoxyphenyl)-4-cyano-1-(3-methyl[1.2.4]oxadiazol-5-yl)cyclohexane1

A solution ofcis-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxamide](0.06 g, 0.17 mmol) in N,N-dimethylacetamide dimethyl acetal (0.5 mL)was heated at 110° C. under an argon atmosphere for 1 h, was cooled andthe solvent was evaporated. Dioxane (0.35 mL), acetic acid (0.35 mL),hydroxylamine hydrochloride (0.02 g, 0.29 mmol) and 10% aqueous sodiumhydroxide (0.09 mL, 0.26 mmol) were added and the mixture was heated at95° C. under an argon atmosphere for 2.5 h. The mixture was cooled,water was added, the mixture was extracted three times with methylenechloride, the organic extract was dried (magnesium sulfate) and wasevaporated. Purification by flash chromatography, eluting with 4%methanol/methylene chloride, provided a solid (0.03 g, 37%). Thisproduct was combined with that (0.04 g) from a similar reaction sequenceand was triturated with hexane to yield a tan solid: m.p. 83°-84° C.

Analysis Calc. for C₁₈ H₁₇ F₄ N₃ O₃ : C 54.14, H 4.29, N 10.52; found: C54.11, H 4.35, N 10.13.

EXAMPLE 12cis-{4-(3,4-Bisdifluoromethoxyphenyl)-4-cyano-1-(2-methyl[1,3,4]oxadiazol-5-yl)cyclohexane]

cis-[4(3,4-Bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carbohydrazide]

A solution of methylcis-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carboxylate](0.2 g, 0.53 mmol) and hydrazine hydrate (0.28 mL, 9.0 mmol) in ethanol(2.5 mL) was heated at reflux for 6 h and then stirred at roomtemperature for 16 h. Water was added, the mixture was extracted threetimes with methylene chloride, the extract was dried (magnesium sulfate)and evaporated. Purification by flash chromatography, eluting with 4%methanol/methylene chloride, provided a solid (0.12 g, 58%): m.p.80°-81° C.

cis-[4-(3,4-Bisdifluoromethoxyphenyl)-4cyanocyclohexane-1(2-acetyl-carbohydrazide)]

A solution of methylcis-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-carbohydrazide](0.11g, 0.29 mmol) triethylamine (0.09 mL, 0.65 mmol) and acetic anhydride(0.05 mL, 0.54 mmol) in ethanol (7.5 mL) was heated at reflux for 1 h,was cooled and the solvent was evaporated. Water was added, the mixturewas extracted three times with methylene chloride, the extract was dried(magnesium sulfate) and evaporated to provide a white solid (0.11 g,85%): m.p. 144°-145° C.

cis-{4-(3,4-Bisdifluoromethoxyphenyl)-4-cyano-1-(3-methyl[1,3,4]oxadiazol-5-yl)cyclohexane}

A solution ofcis-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-(2-acetyl-carbohydrazide)](0.1 g, 0.24 mmol) and phosphorpus oxychloride (0.25 mL, 2.68 mmol) intoluene (3 mL) was heated at reflux under an argon atmosphere for 1.5 h.The mixture was cooled, water was added, the mixture was extracted threetimes with 5% methanol/methylene chloride, the organic extract was dried(magnesium sulfate) and was evaporated. Purification by flashchromatography, eluting with 1:2 hexanes/ethyl acetate, provided an oil.

Analysis Calc. for C₁₈ H₁₇ F₄ N₃ O₃.1.0 H₂ O: C 51.80, H 4.59, N 10.07;found: C 52.00, H 4.25, N 9.76.

EXAMPLE 13cis-4-(3,4-Bisdifluoromethoxyphenyl)-4-cyano-1-(2-methyl[1,3,4]thiadiazol-5-yl)cyclohexane}

A solution ofcis-[4-(3,4-bisdifluoromethoxyphenyl)-4-cyanocyclohexane-1-(2-acetyl-carbohydrazide)](0.1 g, 0.24 mmol) and Lawesson's Reagent (0.13 g, 0.32 mmol) in toluene(3 mL) was heated at reflux under an argon atmosphere for 0.5 h. Themixture was cooled, saturated aqueous sodium bicarbonate was added, themixture was extracted three times with methylene chloride, the organicextract was dried (magnesium sulfate) and was evaporated. Purificationby flash chromatography, eluting with 1:1 hexanes/ethyl acetate,provided a solid: m.p. 66°-67° C.

Analysis Calc. for C₁₈ H₁₇ F₄ N₃ O₂ S: C 52.04, H 4.13, N 10.12; found:C 51.67, H 4.06, N 9.92.

EXAMPLE 14cis-[4-Cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxy-1-tris(methylthio)methylcyclohexane]

n-Butyllithium (1.9M in hexanes, 0.4 mL, 0.76 mmol) was added dropwiseover 5 min to a solution of tris(methylthio)methane (0.11 mL, 0.83 mmol)in dry tetrahydrofuran (3 mL) at -78° C. under an argon atmosphere.After 15 min, a solution of4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane (0.2 g, 0.67mmol) in dry tetrahydrofuran (3 mL) was added dropwise over 10 min.After 0.5 h, aqueous ammonium chloride was added and the mixture wasallowed to warm to room temperature. The mixture was extracted threetimes with methylene chloride, the organic extract was dried (magnesiumsulfate) and evaporated. Purification by flash chromatography, elutingwith 25% ethyl acetate/hexanes, provided a white solid (0.25 g, 84%):m.p. 123°-124° C.

Analysis Calc. for C₂₂ H₃₁ NO₃ S₃ : C 58.24, H 6.89, N 3.09; found: C58.57, H 6.81, N 2.92.

EXAMPLE 15 Methylcis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylate]

Mercuric chloride (0.23 g, 0.85 mmol) and mercuric oxide (0.08 g, 0.37mmol) were added to a solution ofcis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxy-1-tris(methylthio)methylcyclohexane](0.1g, 0.22 mmol) in 12:1 methanol/water (2 mL) under an argon atmosphereand the mixture was allowed to stir at room temperature for 4 h. Themixture was filtered through Celite, the filtrate was diluted with waterand was extracted three times with methylene chloride, the organicextract was dried (magnesium sulfate) and was evaporated. Purificationby flash chromatography, eluting with 35% ethyl acetate/hexanes,provided a sticky solid (0.67 g), which was triturated with ether/hexaneto provide a solid (0.47 g, 59%): m.p. 102°-103° C.

Analysis Calc. for C₂₀ H₂₅ NO₅.1/2 H₂ O: C 65.20, H 7.11, N 3.80; found:C 65.31, H 6.83, N 3.54.

EXAMPLE 16cis-[4-Cyano-4-(3cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylicacid]

The title compound, prepared substantially as described above forcis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid] in EXAMPLE 5, was isolated as a solid: m.p. 168°-169° C.

Analysis Calc. for C₁₉ H₂₃ NO₅ 1/4 H₂ O: C 65.22, H 6.77, N 4.00: found:C 64.94, H 6.62, N 3.80.

EXAMPLE 17cis-[4-Cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxamide]

A solution ofcis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxy-phenyl)-1-hydroxycyclohexane-1-carboxylicacid] (0.15 g, 0.42 mmol) and a trace of sodium cyanide in methanol (1.5mL) contained in a pressure vessel was cooled to -78 and anhydrousammonia (2 mL) was condensed into the tube. The tube was sealed, wasallowed to come to room temperature and the reaction was stirred for 2days. The ammonia was allowed to evaporate and the reaction waspartitioned between water and methylene chloride. The organic extractwas dried (magnesium sulfate) and the solvent was evaporated.Purification by flash chromatography, eluting with 3%methanol/chloroform, provided a solid (0.054 g, 38%): m.p. 144°-145° C.

Analysis Calc. for C₉ H₂₄ N₂ O₄.1/4 H₂ O: C 65.41, H 7.08, N 8.03;found: C 65.16, H 6.96, N 7.86.

EXAMPLE 18 Methylcis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxylate]

Silver (I) oxide (0.62 g, 2.7 mmol) was added to a solution of methylcis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylate](0.62g, 1.7 mmol) and iodomethane (5 mL) in acetonitrile (5 mL) under anargon atmosphere and the mixture was heated at reflux in the dark for 18h. The mixture was cooled, was filtered through Celite and the filtratewas evaporated. Purification by flash chromatography, eluting with 20%ethyl acetate/hexanes, provided a solid (0.55 g, 86%): m.p. 75°-76° C.

Analysis Calc. for C₂₁ H₂₇ NO₅ : C 67.54, H 7.29, N 3.75; found: C67.46, H 7.30, N 3.80.

EXAMPLE 19cis-[4-Cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxylicacid]

The title compound, prepared substantially as described above forcis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid] in EXAMPLE 5was as a solid: m.p. 110°-112° C.

Analysis Calc. for C₂₀ H₂₅ NO₅ : C 66.84, H 7.01, N 3.90; found: C66.64, H 7.29, N 3.95.

EXAMPLE 20

cis-14-Cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxamide]

A solution ofcis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxylicacid] (0.13 g, 0.36 mmol) and N-methylmorpholine (0.05 mL, 0.45 mmol) in1,2-dimethoxyethane (2.5 mL) at room temperature under an argonatmosphere was treated with isobutyl chloroformate (0.05 mL, 0.39 mmol).After 10 min, concentrated ammonium hydroxide (6 drops) was added andthe mixture was stirred for an additional 0.5 h. Water was added, themixture was extracted three times with 5% methanol/methylene chloride,the organic extract was dried (magnesium sulfate) and the solvent wasevaporated. Purification by flash chromatography, eluting with 3%methanol/chloroform, provided a solid (0.13 g, 100%): m.p. 165°-166° C.

Analysis Calc. for C₂₀ H₂₆ N₂ O₄.3/8 H₂ O: C 65.78, H 7.35, N 7.67;found: C 65.65, H 7.23, N 7.47.

EXAMPLE 21 Methyltrans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylate]

trans-[4-Cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-cyclohexane-1,1-diyl]oxirane]

To a mixture of 80% sodium hydride in mineral oil (0.33 g, 11 mmol) andtrimethylsulfoxonium iodide (1.69 g, 7.67 mmol) at room temperatureunder an argon atmosphere was added dropwise dimethylsulfoxide (12 mL)and the reaction mixture was stirred for 30 min. A solution of4-cyano-4-(3-cyclopropylmethoxy-3-methoxyphenyl) -cyclohexanone (2.00 g,6.68 mmol) in dimethylsulfoxide (5 mL) was added and stirring wascontinued for 30 min. The reaction mixture was quenched with saturatedammonium chloride, was partitioned between ethyl acetate and water, wasdried (magnesium sulfate) and the solvent was removed in vacuo. Theresidue was purified by flash chromatography, eluting with 1:3 ethylacetate/hexanes, to provide a colorless oil (1.42 g, 68%).

Analysis Calc. for C₁₉ H₂₃ NO₃.H₂ O: C 68.86, H 7.30, N 4.23; found: C69.22, H 7.11, N 4.17. Starting material was also recovered (0.6 g,30%).

5trans-[4-Cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxymethyl-1-cyclohexanol]

A mixture oftrans-4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)cyclohexane-1-methyleneoxide(1.31 g, 4.18 mmol) and potassium hydroxide (0.14 g, 2.5 mmol) in 85:15dimethylsulfoxide/water (140 mL) under an argon atmosphere was heated at100°-110° C. for 1 h, was cooled, was diluted with water and wasextracted three times with ethyl acetate. The organic extract was washedfive times with water, was dried (magnesium sulfate) and was evaporated.Purification by flash chromatography, eluting with 3.5:96.5methanol/dichloromethane, provided the trans-isomer as a sticky whitesolid: m.p. 38°-42° C. (0.96 g, 69%).

Analysis Calc. for C₁₉ H₂₅ NO₄ : C 68.86, H 7.60, N 4.23; found: C68.96, H 7.62, N 4.03.

trans-[4-Cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxaldehyde]

To a solution of oxalyl chloride (0.28 mL, 3.21 mmol) in dichloromethane(3.5 mL) at -78° C. under an argon atmosphere was added dropwise asolution of dimethylsulfoxide (0.46 mL, 6.48 mmol) in dichloromethane(3.5 mL) such that the internal temperature did not exceed -60° C. Asolution oftrans-4-cyano-4-(3-cyclopropylmethoxy-3-methoxyphenyl)-1-hydroxymethyl-1-cyclohexanol(0.89 g, 2.68 mmol) in dichloromethane (7 mL) was added dropwise andstirring was continued for 30 min. Triethylamine (1.80 mL, 12.9 mmol)was added over 10 min, then 5 min later, the reaction mixture wasallowed to warm to room temperature over 1 h. The reaction mixture wasquenched with water and was extracted with three portions ofdichloromethane. The combined organic layers were washed with 1%hydrochloric acid, 5% sodium carbonate and water, dried (magnesiumsulfate) and the solvent was removed in vacuo to provide crude aldehyde(0.85 g, 97 %).

Methyl trans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylate

To a solution oftrans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxaldehyde(0.79 g, 2.4 mmol) in methanol (25 mL) at 0° C. under an argonatmosphere was rapidly added a solution of potassium hydroxide (0.36 g,6.43 mmol) in methanol (5 mL), followed by a solution of iodine (0.80 g,3.15 mmol) in methanol (5 mL). After 15 min the reaction was acidifiedwith 1N hydrochloric acid and extracted with three portions ofdichloromethane. The combined organic layers were washed with aqueoussodium bisulfite until color was discharged, then with water, dried(magnesium sulfate), and the solvent was removed in vacuo. Purificationby flash chromatography, eluted with 35:65 ethyl acetate/hexanes,provided a white solid (0.82 g, 94 %): m.p. 148°-149° C.

Analysis Calc. for C₂₀ H₂₅ NO₅.1/4 H₂ O: C 66.01, H 7.06, N 3.84; found:C 65.86, H 6.92, N 3.85.

EXAMPLE 22 4trans-[4-Cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-hydroxycyclohexane-1-carboxylicacid]

The title compound, prepared substantially as described above forcis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid] in EXAMPLE 5, was isolated as a solid: m.p. 147°-148° C.

Analysis Calc. for C₁₉ H₂₃ NO₅ : C 66.07, H 6.71, N 4.06; found: C66.02, H 6.71, N 4.04.

EXAMPLE 23 Methyltrans-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxylate]

The title compound, prepared substantially as described above for methylcis-[4-cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxylate]in EXAMPLE 18, was isolated as a solid: m.p. 84°-85° C.

Analysis Calc. for C₂₁ H₂₇ NO₅ : C 67.54, H 7.29, N 3.75; found: C67.34, H 7.25, N 3.77.

EXAMPLE 24trans-[4-Cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxylicacid]

The title compound, prepared substantially as described above forcis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid] in EXAMPLE 5, was isolated as a solid: m.p. 158°-159° C.

Analysis Calc. for C₂₀ H₂₅ NO₅.1/4 H₂ O: C 66.01, H 7.06, N 3.85; found:C 65.98, H 6.91, N 3.75.

EXAMPLE 25trans-[4-Cyano-4-(3-cyclopropylmethoxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxamide]

The title compound, prepared substantially as described above forcis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxamide]in EXAMPLE 20, was isolated as a solid: m.p. 168°-169° C.

Analysis Calc. for C₂₀ H₂₆ N₂ O₄.1/8 H₂ O: C 66.60, H 7.34, N 7.70;found: C 66.60, H 7.30, N 7.74.

EXAMPLE 26cis[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxamicacid]

The title compound, prepared substantially as described above forcis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxamide]in EXAMPLE 20 but using hydroxylamine instead of ammonia, was isolatedas a solid: m.p. 100°-102° C.

Analysis Calc. for C₂₀ H₂₆ N₂ O₄ : C 67.02, H 7.31, N 7.82; found: C66.75, H 7.58, N 7.42.

EXAMPLE 27N-Methyl-cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxamicacid]

The title compound, prepared substantially as described above forcis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-1-methoxycyclohexane-1-carboxamide]in EXAMPLE 20 but using N-methylhydroxylamine instead of ammonia, wasisolated as a solid: m.p. 75°-76° C.

Analysis Calc. for C₂₁ H₂₈ N₂ O₄.1/4 H₂ O: C 66.91, H 7.62, N 7.43;found: C 66.95, H 7.54, N 7.35.

EXAMPLE 28cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-N-(2-cyanoethyl)carboxamide]

To a solution ofcis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylicacid] (0.55 g, 1.6 mmol), 1-hydroxybenzotriazole (0.24 g, 1.76 mmol) and3-aminopropionitrile (0.11 g, 1.6 mmol) in dichloromethane (10 mL) at 0°C. under an argon atmosphere was added1-(3-diethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.34 g, 1.76mmol) and the mixture was allowed to warm to room temperature. After 6h, the mixture was diluted with dichloromethane, was washed twice with10% aqueous potassium carbonate, twice with 10 % hydrochloric acid andwas dried (magnesium sulfate). The solvent was evaporated and theresidue was crystallized from hexanes/ethyl acetate to provide a solid(0.54 g, 85%): m.p. 146°-147° C.

Analysis Calc. for C₂₃ H₂₉ N₃ O₃ : C 69.85, H 7.39, N 10.62; found: C69.49 H 7.41, N 10.46.

EXAMPLE 29cis-[1-(2-Cyanoethyl)-5-{4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexyl}tetrazole]

To a solution ofcis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-N-(2-cyanoethyl)carboxamide](0.15 g, 0.37 mmol), triphenylphosphine (0.19 g, 0.73 mmol) andtrimethylsilylazide (0.097 mL, 0.73 mmol) in dry, tetrahydrofuran (2 mL)at room temperature under an argon atmosphere was added dropwise diethylazodicarboxylate (0.12 mL, 0.73 mmol) and the mixture was stirred in thedark for 24 h. Ceric ammonium nitrate (0.81 g, 1.48 mmol) in water (10mL) was added at 0° C., the mixture was extracted three times withdichloromethane, the extract was dried (magnesium sulfate) and thesolvent was evaporated. Purification by flash chromatography, elutingwith 2:1 ethyl acetate/hexanes, followed by recrystallization fromhexanes/ethyl acetate, provided a white solid (0.03 g, 19%): m.p.149°-150° C.

Analysis Calc. for C₂₃ H₂₈ N₆ O₂ : C 65.69, H 6.71, N 19.99; found: C65.45 H 6.72, N 19.91.

EXAMPLE 30cis-[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)-1-(5-tetrazolyl)cyclohexane]

A mixture ofcis-[1-(2-cyanoethyl)-5-{4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexyl}tetrazole](0.098g, 0.23 mmol) and sodium hydroxide (0.018 g, 0.46 mmol) in 10:1tetrahydrofuran/water (5 mL) at room temperature under an argonatmosphere was stirred overnight. The mixture was acidified with 3Nhydrochloric acid, was extracted three times with ethyl acetate, theextract was dried (magnesium sulfate) and the solvent was evaporated.Purification by flash chromatography, eluting with 80:20:2chloroform/methanol/water, followed by trituration with hexanes/ethylacetate, provided a white solid (0.038 g, 45%): m.p. 190°-191° C.

Analysis Calc. for C₂₀ H₂₅ N₅ O₂.1/2 H₂ O: C 63.81, H 6.96, N 18.60;found: C 64.07 H 6.79, N 18.54.

METHODS OF TREATMENT

In order to use a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof for the treatment of humans and other mammals,it is normally formulated in accordance with standard pharmaceuticalpractice as a pharmaceutical composition. The compounds of Formula (I)or a pharmaceutically acceptable salt thereof can be used in themanufacture of a medicament for the prophylactic or therapeutictreatment of any disease state in a human or other mammal which ismediated by inhibition of PDE IV, such as but not limited to asthma,allergic, or inflammatory diseases. The compounds of Formula (I) areadministered in an amount sufficient to treat such a disease in a humanor other mammal.

The method of treatment and monitoring for an HIV-infected humanmanifesting immune dysfunction or cytokine-mediated disease associatedproblems is taught in Hanna, WO 90/15534, Dec. 27, 1990. In general, aninitial treatment regimen can be copied from that known to be effectivein interfering with TNF activity for other TNF mediated disease statesby the compounds of Formula (I). Treated individuals will be regularlychecked for T cell numbers and T4/T8 ratios and/or measures of viremiasuch as levels of reverse transcriptase or vital proteins, and/or forprogression of monokine-mediated disease associated problems such ascachexia or muscle degeneration. If no effect is seen following thenormal treatment regimen, then the amount of the monokine activityinterfering agent administered is increased, e.g., by fifty percent perweek.

The pharmaceutical composition Of the present invention will comprise aneffective, non-toxic amount of a compound of Formula (I) and apharmaceutically acceptable carder or diluent. The compounds of Formula(I) are administered in conventional dosage forms prepared by combininga compound of Formula (I) in an amount sufficient to produce TNFproduction inhibiting activity, respectively, with standardpharmaceutical carriers according to conventional procedures. Theseprocedures may involve mixing, granulating, and compressing ordissolving the ingredients as appropriate to the desired preparation.

Thus, if a solid carrier is used, the preparation can be tableted,placed in a hard gelatin capsule in powder or pellet form, or in theform of a troche or lozenge. The amount of solid carrier will varywidely but preferably will be from about 25 mg to about 1 gram. When aliquid carrier is used, the preparation will be in the form of a syrup,emulsion, soft gelatin capsule, sterile injectable liquid such as anampule or nonaqueous liquid suspension. Where the composition is in theform of a capsule, any routine encapsulation is suitable, for example,using the aforementioned carriers in a hard gelatin capsule shell. Wherethe composition is in the form of a soft gelatin shell capsule anypharmaceutical carrier routinely used for preparing dispersions orsuspensions may be considered, for example aqueous gums, celluloses,silicates, or oils and are incorporated in a soft gelatin capsule shell.A syrup formulation will generally consist of a suspension or solutionof the compound or salt in a liquid carrier for example, ethanol,glycerine, or water with a flavoring or coloring agent.

The daily dosage regimen for oral administration is suitably about 0.001mg/kg to 100 mg/kg, preferably 0.01 mg/Kg to 40 mg/Kg, of a compound ofFormula (I) or a pharmaceutically acceptable salt thereof calculated asthe free base. The active ingredient may be administered from 1 to 6times a day, sufficient to exhibit activity.

While it is possible for an active ingredient to be administered neat,it is preferable to present it as a pharmaceutical formulation. Theactive ingredient may comprise, for topical administration, from 0.001%to 10% w/w, e.g., from 1% to 2% by weight of formulation, although itmay comprise as much as 10% w/w but preferably not in excess of 5% w/wand more preferably from 0.1% to 1% w/w of Formulation.

Formulations of the present invention comprise an active ingredienttogether with one or more acceptable carrier(s) thereof and optionallyany other therapeutic ingredient(s). The carrier(s) must be `acceptable`in the sense of being compatible with the other ingredients ofFormulation and not deleterious to the recipient thereof.

It will be recognized by one of skill in the art that the form andcharacter of the pharmaceutically acceptable carrier or diluent isdictated by the amount of active ingredient with which it is to becombined, the route of administration, and other well-known variables.

No toxic effects are expected when these compounds are administered inaccordance with the present invention.

UTILITY EXAMPLES EXAMPLE A

Inhibitory effect of compounds of the Formula (I) on in vitro TNFproduction by human monocytes

The inhibitory effect of compounds of the Formula (I) on in vitro TNFproduction by human monocytes may be determined by the protocol asdescribed in Badger et al., EPO published Application 0 411 754 A2, Feb.6, 1991, and in Hanna, WO 90/15534, Dec. 27, 1990.

EXAMPLE B

Two models of endotoxic shock have been utilized to determine in vivoTNF activity for the compounds of the Formula (I). The protocol used inthese models is described in Badger et al., EPO published Application 0411 754 A2, Feb. 6, 1991, and in Hanna, WO 90/15534, Dec. 27, 1990.

The exemplified compounds herein demonstrated a positive in vivoresponse in reducing serum levels of TNF induced by the injection ofendotoxin.

EXAMPLE C Isolation of PDE Isozymes

The phosphodiesterase inhibitory activity and selectivity of thecompounds of the Formula (I) can be determined using a battery of fivedistinct PDE isozymes. The tissues used as sources of the differentisozymes are as follows: 1) PDE Ib, porcine aorta; 2) PDE Ic, guinea-pigheart; 3) PDE III, guinea-pig heart; 4) PDE IV, human monocyte; and 5)PDE V (also called "Ia"), canine tracheaolis. PDEs Ia, Ib, Ic and IIIare partially purified using standard chromatographic techniques [Torphyand Cieslinski, Mol. Pharmacol., 37:206-214, 1990]. PDE IV is purifiedto kinetic homogeneity by the sequential use of anion-exchange followedby heparin-Sepharose chromatography [Torphy et at., J. Biol. Chem.,267:1798-1804, 1992].

Phosphodiesterase activity is assayed as described in the protocol ofTorphy and Cieslinski, Mol. Pharmacol., 37:206°-214, 1990. Positive IC₅₀'s in the nanomolar to μM range for compounds of the workings examplesdescribed herein for Formula (I) have been demonstrated.

EXAMPLE D

The ability of selected PDE IV inhibitors to increase cAMP accumulationin intact tissues is assessed using U-937 cells, a human monocyte cellline that has been shown to contain a large amount of PDE IV. To assessthe activity of PDE IV inhibition in intact cells, nondifferentiatedU-937 cells (approximately 10⁵ cells/reaction tube) were incubated withvarious concentrations (0.01°-1000 μM) of PDE inhibitors for one minuteand 1 μM prostaglandin E2 for an additional four minutes. Five minutesafter initiating the reaction, cells were lysed by the addition of 17.5%perchloric acid, the pH was neutralized by the addition of 1M potassiumcarbonate and cAMP content was assessed by RIA. A general protocol forthis assay is described in Brooker et al., Radioimmunassay of cyclic AMPand cyclic GMP., Adv. Cyclic Nucleotide Res., 10:1-33, 1979. Thecompounds of the working examples as described herein for Formula (I)have demonstrated a positive EC₅₀ s in the μM range in the above assay.

What is claimed is:
 1. A compound of Formula (I): ##STR7## wherein: R₁is --(CR₄ R₅)_(n) C(O)O(CR₄ R₅)_(m) R₆, --(CR₄ R₅)_(n) C(O)NR₄ (CR₄R₅)_(m) R₆, --(CR₄ R₅)_(n) O(CR₄ R₅)_(m) R₆, or --(CR₄ R₅)_(r) R₆wherein the alkyl moieties may be optionally substituted with one ormore halogens;m is 0 to 2; n is 1 to 4; r is 0 to 6; R₄ and R₅ areindependently selected from hydrogen or a C₁₋₂ alkyl; R₆ is hydrogen,methyl, hydroxyl, aryl, halo substituted aryl, aryloxy C₁₋₃ alkyl, halosubstituted aryloxy C₁₋₃ alkyl, indanyl, indenyl, C₇₋₁₁ polycycloalkyl,tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl,tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C₃₋₆cycloalkyl, or a C₄₋₆ cycloalkyl containing one or two unsaturatedbonds, wherein the cycloalkyl and heterocyclic moieties may beoptionally substituted by 1 to 3 methyl groups or one ethyl group;provided that:a) when R₆ is hydroxyl, then m is 2; or b) when R₆ ishydroxyl, then r is 2 to 6; or c) when R₆ is 2-tetrahydropyranyl,2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl,then m is 1 or 2; or d) when R₆ is 2-tetrahydropyranyl,2-tetrahydrothiopyranyl, 2-tetrahydrofuranyl, or 2-tetrahydrothienyl,then r is 1 to 6; e) when n is 1 and m is 0, then R₆ is other than H in--(CR₄ R₅)_(n) O(CR₄ R₅)_(m) R₆ ; X is YR₂, halogen, nitro, NR₄ R₅, orformyl amine; Y is O or S(O)m'; m' is 0, 1, or 2; X₂ is O or NR₈ ; X₃ ishydrogen or X; X₄ is ##STR8## X₅ is H, R₉, OR₈, CN, C(O)R₈, C(O)OR₈,C(O)NR₈ R₈, or NR₈ R₈ ; R₂ is independently selected from the groupconsisting of --CH₃ and --CH₂ CH₃ optionally substituted by 1 or morehalogens; s is 0 to 4; R₃ is --CH═CR_(8') R_(8'), Z is C(Y')R₁₄,C(O)OR₁₄, C(Y')NR₁₀ R₁₄, C(NR₁₀)NR₁₀ R₁₄, CN, C(NOR₈)R₁₄, C(O)NR₈ NR₈C(O)R₈, C(O)NR₈ NR₁₀ R₁₄, C(NOR₁₄)R₈, C(NR₈)NR₁₀ R₁₄, C(NR₁₄)NR₈ R₈C(NCN)NR₁₀ R₁₄, C(NCN)SR₉, (2-, 4- or 5-imidazolyl), (3-, 4- or5-pyrazolyl), (4- or 5-triazolyl(1,2,3), (3- or 5-triazolyl(1,2,4),(5-tetrazolyl), (2-, 4- or 5-oxazolyl), (3-, 4- or 5-isoxazolyl), (3- or5-oxadiazolyl(1,2,4), (2-oxadiazolyl(1,3,4), (2-thiadiazolyl(1,3,4),(2-, 4-, or 5-thiazolyl), (2-, 4-, or 5-oxazolidinyl), (2-, 4-, or5-thiazolidinyl), or (2-, 4-, or 5-imidazolidinyl); wherein all of theheterocylic ring systems may be optionally substituted one or more timesby R₁₄ ; the dotted line in formula (a) represents a single or doublebond; Y' is 0 or S; R₇ is --(CR₄ R₅)_(q) R₁₂ or C₁₋₆ alkyl wherein theR₁₂ or C₁₋₆ alkyl group is optionally substituted one or more times byC₁₋₂ alkyl optionally substituted by one to three fluorines, --F, --Br,--Cl, --NO₂, --NR₁₀ R₁₁, --C(O)R₈, --C(O)OR₈, --OR₈, --CN, --C(O)NR₁₀R₁₁, --OC(O)NR₁₀ R₁₁, --OC(O)R₈, --NR₁₀ C(O)NR₁₀ R₁₁, --NR₁₀ C(O)R₁₁,--NR₁₀ C(O)OR₉, --NR₁₀ C(O)R₁₃, --C(NR₁₀)NR₁₀ R₁₁, --C(NCN)NR₁₀ R₁₁,--C(NCN)SR₉, --NR₁₀ C(NCN)SR₉, --NR₁₀ C(NCN)NR₁₀ R₁₁, --NR₁₀ S(O)₂ R₉,--S(O)m' R₉, --NR₁₀ C(O)C(O)NR₁₀ R₁₁ --NR₁₀ C(O)C(O)R₁₀, thiazolyl,imidazolyl, oxazolyl, pyrazolyl, triazolyl, or tetrazolyl; q is 0, 1, or2; R₁₂ is C₃ -C₇ -cycloalkyl, (2-, 3- or 4-pyridyl), pyrimidyl,pyrazolyl, (1- or 2-imidazolyl), thiazolyl, triazolyl, pyrrolyl,piperazinyl, piperidinyl, morpholinyl, furanyl, (2- or 3-thienyl), (4-or 5-thiazolyl), quinolinyl, naphthyl, or phenyl; R₈ is independentlyselected from hydrogen or R₉ ; R_(8') is R₈ or fluorine; R₉ is C₁₋₄alkyl optionally substituted by one to three fluorines; R₁₀ is OR₈ orR₁₁ ; R₁₁ is hydrogen, or C₁₋₄ alkyl optionally substituted by one tothree fluorines; or when R₁₀ and R₁₁ are as NR₁₀ R₁₁ they may togetherwith the nitrogen form a 5 to 7 membered ring optionally containing atleast one additional heteroatom selected from O,N or S; R₁₃ isoxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl,imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, orthiadiazolyl, and each of these heterocyclic rings is connected througha carbon atom and each may be unsubstituted or substituted by one or twoC₁₋₂ alkyl groups; R₁₄ is hydrogen or R₇ ; or when R₁₀ and R₁₄ are asNR₁₀ R₁₄ they may together with the nitrogen form a 5 to 7 membered ringoptionally containing one or more additional heteroatoms selected fromO, N, or S; provided that:f) when R₁₂ is N-pyrazolyl, N-imidazolyl,N-triazolyl, N-pyrrolyl, N-piperazinyl, N-piperidinyl, or N-morpholinyl,then q is not 1; or or the pharmaceutically acceptable salts thereof. 2.A pharmaceutical composition comprising a compound of Formula (I)according to claim 1 and a pharmaceutically acceptable excipient.
 3. Amethod for treating an allergic or inflammatory disease which methodcomprises administering to a subject in need thereof an effective amountof a compound of Formula (I) according to claim 1 alone or incombination with a pharmaceutically acceptable excipient.